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Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

Postal Subscription Code 80-967

2018 Impact Factor: 1.847

Front. Med.    2015, Vol. 9 Issue (3) : 288-303     DOI: 10.1007/s11684-015-0412-0
REVIEW |
Toll-like receptor signaling in hematopoietic homeostasis and the pathogenesis of hematologic diseases
Joseph Cannova1,2,Peter Breslin S.J.3,5,6,*(),Jiwang Zhang1,3,4,*()
1. Biochemistry and Molecular Biology Program, Loyola University Chicago, Maywood, IL 60153, USA
2. Stritch School of Medicine, Loyola University Chicago, Maywood, IL 60153, USA
3. Oncology Institute, Loyola University Chicago, Maywood, IL 60153, USA
4. Department of Pathology, Loyola University Chicago, Maywood, IL 60153, USA
5. Department of Biology, Loyola University Chicago, Chicago, IL 60660, USA
6. Department of Molecular and Cellular Physiology, Loyola University Chicago, Maywood, IL 60153, USA
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Abstract  

Toll-like receptors (TLRs), which are found in innate immune cells, are essential mediators of rapid inflammatory responses and appropriate T-cell activation in response to infection and tissue damage. Accumulating evidence suggests that TLR signaling is involved in normal hematopoiesis and specific hematologic pathologies. Particular TLRs and their downstream signaling mediators are expressed not only in terminally differentiated innate immune cells but also in early hematopoietic progenitors. Sterile activation of TLR signaling is required to generate early embryonic hematopoietic progenitor cells. In adult animals, TLR signaling directly or indirectly promotes differentiation of myeloid cells at the expense of that of lymphoid cells and the self-renewal of hematopoietic stem cells during infection and tissue damage. Activating mutations of the MyD88 gene, which codes for a key adaptor involved in TLR signaling, are commonly detected in B-cell lymphomas and other B-cell hematopathologies. Dysregulated TLR signaling contributes to the pathogenesis of many hematopoietic disorders, including bone marrow failure, myelodysplastic syndrome, and acute myeloid leukemia. Complete elucidation of the molecular mechanisms by which TLR signaling mediates the regulation of both normal and pathogenic hematopoiesis will prove valuable to the development of targeted therapies and strategies for improved treatment of hematopoietic disorders.

Keywords TLR      MyD88      hematopoiesis      bone marrow failure      leukemia      myelodysplastic syndrome     
Corresponding Authors: Peter Breslin S.J.,Jiwang Zhang   
Just Accepted Date: 12 August 2015   Online First Date: 21 August 2015    Issue Date: 26 August 2015
URL:  
http://academic.hep.com.cn/fmd/EN/10.1007/s11684-015-0412-0     OR     http://academic.hep.com.cn/fmd/EN/Y2015/V9/I3/288
Fig.1  TLR signaling ligands and directed responses. TLR signaling is divided into MyD88-dependent and MyD88-independent responses. MyD88-dependent signaling mediates the activation of IL1R, TLR1/2, TLR2/6, TLR4, TLR5, TLR7, TLR8, and TLR9. Such activation leads to oligomerization of the myddosome, which is composed of MyD88, IRAK1/2, and IRAK4. The myddosome activates TRAF6, which results in the activation of p38/CREB, JNK/AP-1, and NF-κB transcription factors, thereby stimulating inflammatory cytokine production. TLR7, TLR8, and TLR9 dimerization and signaling have been consolidated in this figure. In addition to myddosome signaling, TLR7, TLR8, and TLR9 induce IRF5 and IRF7 activation through TRAF6, indicated by the dashed line. TLR1, TLR 2, TLR4, TLR5, TLR6, and IL1R are unable to induce IFN expression through MyD88. MyD88-independent (TRIF-dependent) signaling mediates type I interferon production through the activation of IRF3 and IRF7. TRIF is suppressed through a direct interaction with SARM. TRIF may also bind to RIPK3 to initiate necroptosis, which is normally suppressed by caspase-8.
Fig.2  Emergency myelopoiesis in response to TLR activation. Production of myeloid cells is observed in response to TLR stimulation at the level of: (1) peripheral innate immune cells, (2) mesenchymal stem cells (MSCs), and (3) hematopoietic stem cells (HSCs). Upon TLR stimulation, IFN-γ produced by peripheral immune cells migrating to the bone marrow niche stimulates IL-6 production by MSCs, which induces HSPC proliferation and myeloid-biased differentiation.
Fig.3  TLR signaling in hematological pathologies. Aplastic anemia (AA) autoimmune bone marrow failure is mediated by HSPC-reactive Th1 cells. Myelodysplastic syndromes result in ineffective hematopoiesis through alteration of the HSPC microenvironment by myeloid-derived suppressor cells (MDSCs). MDSCs suppress the Th1 T-cell response and produce cytokines that generate a BM microenvironment favorable for leukemic cells.
Fig.4  MyD88 mutations in B-cell lymphomas. Activating mutations of MYD88 in B-cell lymphomas lead to constitutive activation of NF-κB signaling, which promotes proliferation and survival of tumor cells by collaborating with STAT3 signaling stimulated by autocrine inflammatory cytokines.
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